Submissions for variant NM_000218.3(KCNQ1):c.1702G>A (p.Gly568Arg)

dbSNP: rs199472807

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000505735	SCV000234521	pathogenic	not provided	2023-07-27	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22956155, 21185501, 22949429, 25525159, 19841300, 15840476, 19716085, 23392653, 22581653, 27527004, 27041150, 25854863, 25929701, 25916402, 22885918, 22456477, 36136372, RidaM2023[Preprint])
Ambry Genetics	RCV000250706	SCV000320027	pathogenic	Cardiovascular phenotype	2022-08-29	criteria provided, single submitter	clinical testing	The p.G568R pathogenic mutation (also known as c.1702G>A), located in coding exon 14 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 1702. The glycine at codon 568 is replaced by arginine, an amino acid with dissimilar properties. This mutation has been reported in multiple individuals with long QT syndrome (LQTS) (Tester et al. Heart Rhythm. 2005 May;2(5):507-17; Kapplinger et al. Heart Rhythm. 2009 Sep;6(9):1297-303). In addition, this mutation was seen in a compound heterozygote with LQTS, who also harbored an in-frame deletion of the KCNQ1 gene; her mother and maternal first cousin with QT interval prolongation were heterozygous for the p.G568R alteration (Giudicessi, JR and Ackerman, MJ. Cir Cardiovasc Genet. 2013 Apr;6(2):193-200 ). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Alternate amino acid substitutions, p.G568A and p.G568E, have also been reported in individuals with LQTS (Chen S et al. Clin. Genet., 2003 Apr;63:273-82; Izumi G et al. Pediatr Cardiol, 2016 Jun;37:962-70). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192510	SCV001360699	pathogenic	Long QT syndrome	2021-06-13	criteria provided, single submitter	clinical testing	Variant summary: KCNQ1 c.1702G>A (p.Gly568Arg) results in a non-conservative amino acid change located in the C-terminal domain (IPR013821) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251094 control chromosomes. c.1702G>A has been reported in the literature in multiple individuals affected with Long QT Syndrome (example, Giudicessi_2013, Kapplinger_2009). In one of these reports this variant co-segregated with prolonged QTc interval in a family (Giudicessi_2013). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=3)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001192510	SCV001576433	pathogenic	Long QT syndrome	2024-04-09	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 568 of the KCNQ1 protein (p.Gly568Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with long QT syndrome (PMID: 22456477, 22949429, 22956155, 23392653). ClinVar contains an entry for this variant (Variation ID: 53009). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNQ1 protein function with a positive predictive value of 95%. This variant disrupts the p.Gly568 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been observed in individuals with KCNQ1-related conditions (PMID: 12702160), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000505735	SCV001714961	likely pathogenic	not provided	2020-01-10	criteria provided, single submitter	clinical testing	PS4_Moderate, PM2, PM3, PP1, PP3
Fulgent Genetics, Fulgent Genetics	RCV002496701	SCV002811565	likely pathogenic	Atrial fibrillation, familial, 3; Beckwith-Wiedemann syndrome; Long QT syndrome 1; Jervell and Lange-Nielsen syndrome 1; Short QT syndrome type 2	2021-10-17	criteria provided, single submitter	clinical testing
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000057622	SCV000089141	not provided	Congenital long QT syndrome		no assertion provided	literature only	This variant has been reported as associated with Long QT syndrome in the following publications (PMID:15840476;PMID:19716085;PMID:19841300). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000678815	SCV000805001	pathogenic	not specified	2016-02-29	no assertion criteria provided	clinical testing